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Non-invasive in vivo imaging of early metabolic tumor response to therapies targeting choline metabolism.

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Mignion, Lionel [UCL] Danhier, Pierre [UCL] Magat, Julie [UCL] Porporato, Paolo [UCL] Masquelier, Julien [UCL] Grégoire, Vincent [UCL] Muccioli, Giulio [UCL] Sonveaux, Pierre [UCL] Gallez, Bernard [UCL] Jordan, Bénédicte [UCL]

The cholinic phenotype, characterized by elevated phosphocholine and a high production of total-choline (tCho)-containing metabolites, is a metabolic hallmark of cancer. It can be exploited for targeted therapy. Non-invasive imaging biomarkers are required to evaluate an individual's response to targeted anticancer agents that usually do not rapidly cause tumor shrinkage. Because metabolic changes can manifest at earlier stages of therapy than changes in tumor size, the aim of the current study was to evaluate (1) H-MRS and diffusion-weighted MRI (DW-MRI) as markers of tumor response to the modulation of the choline pathway in mammary tumor xenografts. Inhibition of choline kinase activity was achieved with the direct pharmacological inhibitor H-89, indirect inhibitor sorafenib and down-regulation of choline-kinase α (ChKA) expression using specific short-hairpin RNA (shRNA). While all three strategies significantly decreased tCho tumor content in vivo, only sorafenib and anti-ChKA shRNA significantly repressed tumor growth. The increase of apparent-diffusion-coefficient of water (ADCw) measured by DW-MRI, was predictive of the induced necrosis and inhibition of the tumor growth in sorafenib treated mice, while the absence of change in ADC values in H89 treated mice predicted the absence of effect in terms of tumor necrosis and tumor growth. In conclusion, (1) H-choline spectroscopy can be useful as a pharmacodynamic biomarker for choline targeted agents, while DW-MRI can be used as an early marker of effective tumor response to choline targeted therapies. DW-MRI combined to choline spectroscopy may provide a useful non-invasive marker for the early clinical assessment of tumor response to therapies targeting choline signaling. This article is protected by copyright. All rights reserved.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 2016
Language Anglais
Journal information "International Journal of Cancer" - Vol. 138, no. 8, p. 2043-2049 (2016)
Peer reviewed yes
Publisher Wiley-Liss ((United States) New York, NY)
issn 0020-7136
e-issn 1097-0215
Publication status Publié
Affiliations UCL - SSS/LDRI - Louvain Drug Research Institute
UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie
UCL - (SLuc) Service de radiothérapie oncologique
UCL - SSS/IREC - Institut de recherche expérimentale et clinique
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Bibliographic reference Mignion, Lionel ; Danhier, Pierre ; Magat, Julie ; Porporato, Paolo ; Masquelier, Julien ; et. al. Non-invasive in vivo imaging of early metabolic tumor response to therapies targeting choline metabolism.. In: International Journal of Cancer, Vol. 138, no. 8, p. 2043-2049 (2016)
Permanent URL http://hdl.handle.net/2078.1/167746